وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
Draft Guideline for
Registration of
Biosimilar Products
Page 1 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
Document Control
Date Version Comments
6/12/2012 0.1 Draft for discussion purposes
Members of the Biosimilars Team assigned for the guidelines preparation
Pharmacist/ Mona Mohamed Saleh Head of the Biologicals Registration Directorate
Head of Biosimailars Guidelines Taskforce
Central Administration for Pharmaceutical Affairs
Pharmacist/ Kholoud Mamdouh The Biologicals evaluation committee Team Senior
Rapporteur of Biosimailars Guidelines Taskforce
Central Administration for Pharmaceutical Affairs
Pharmacist/ Khaled Mohammed Amen Biologicals Registration Specialist
Central Administration for Pharmaceutical Affairs
Pharmacist/ Mariam Raouf Biologicals Registration Specialist
Central Administration for Pharmaceutical Affairs
Pharmacist/ Ahmed El-Kholy Biologicals Registration Specialist
Central Administration for Pharmaceutical Affairs
Pharmacist/ Mai Gamal Allam Q.C specialist in Biotechnology subunit
National Organization for Research and Control of Biologics
Pharmacist/ Doaa Hosny Biological Inspector
Central Administration for Pharmaceutical Affairs
Pharmacist/ Safa Taha Ibrahim Member of the Technical office of CAPA Head
Central Administration for Pharmaceutical Affairs
Comments to be send to the Biologicals Registration Directorate by e-mail:
Page 2 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
Contents
Introduction ..................................................................................................................................................... 3
I. Background ............................................................................................................................................ 3
II. Scope........................................................................................................................................................ 3
III. Definitions ............................................................................................................................................... 4
IV. Registration of a biosimilar product .................................................................................................... 4
1- Final dossier approach (for imported products) ................................................................................................ 4
2- Step wise approach (for locally manufactured products) .................................................................................. 5
V. Principles for Development of Biosimilar products ............................................................................ 6
1- Select a reference product ................................................................................................................................. 6
2- Manufacturing Process and Expression system ................................................................................................ 6
VI. Comparability Key elements ................................................................................................................. 7
1- Quality Aspects: ............................................................................................................................................... 7
A. Structural characterization and conformation .......................................................................................8
B. Specifications: Release of DS / DP .....................................................................................................8
C. Final formulation ............................................................................................................................. 10
D. Stability .......................................................................................................................................... 10
2- Preclinical Aspects ......................................................................................................................................... 11
A. Factors affecting design of the preclinical comparability program ............................................................ 11
B. General considerations ............................................................................................................................... 11
C. The minimum pre-clinical studies required for evaluating a biosimilar product ....................................... 11
D. Batches ....................................................................................................................................................... 13
3- Clinical Aspects: ............................................................................................................................................ 13
A. General Considerations .............................................................................................................................. 13
B. Clinical study ............................................................................................................................................. 14
C. Batches ....................................................................................................................................................... 16
D. Extrapolation of indication ......................................................................................................................... 17
VII. Pharmacovigilance ............................................................................................................................... 17
VIII. Glossary ................................................................................................................................................ 18
Reference guidelines ..................................................................................................................................... 19
Page 3 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
Introduction
Regulations for registration of biological products has been recently implemented in Egypt in
2009 through the Minister decree 297/2009 adopting guidelines for submission of registration
dossier based on full data (quality, preclinical and clinical).
This guideline has been developed in order to facilitate the registration of biosimilar products in
Egypt through an abbreviated pathway.
I. Background
The difference between the term generic used for description of copies for reference
pharmaceutical product and the term biosimilar used to describe the similar versions of reference
biological product should be clearly understood.
The demonstration of bioequivalence of the generic medicine with a reference pharmaceutical
product is usually appropriate and sufficient to prove therapeutic equivalence between the generic
medicine and the reference pharmaceutical product.
However, the guidelines for development, evaluation and registration of generic medicines is not
suitable for biological products because biological products consist of relatively large, and complex
proteins that:
1- Are Difficult to characterize / analyze all the quality attributes contributing to the Safety and
Efficacy profile tending to induce an unwanted immune response.
2- Are highly dependent on manufacturing process that affects Product quality, safety & efficacy
profile.
Therefore two approaches for registration of a Similar version of a biological product can be
applied:
1- Stand-alone approach: the manufacturer perform complete product development program
(quality, pre-clincal and clincal studies) (excluded from the scope of this guideline).
2- Biosimilar approach:the manufacturer perform complete product CMC development process in
addition to comparability quality exercise, and reduced preclinical and clinical comparability
studies inorder to demonstrate biosimilarity of the propsed biological product to a reference
biological product.
II. Scope
The scope of this guideline is all biological products intended to be registered as biosimilars
to a reference biological product with exception of blood derived products & their recombinant
analouges, vaccines and sera.
Page 4 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
III. Definitions
Biological product: Medicinal products made of substances extracted from or produced by living
sources whether they are genetically modified living organisms or Liquids and tissues extracted
from various human or animal sources.
Biosmilar: Biological product (other than blood derived products their recombinant analouges, vaccines and
sera) having the same active substance, dosage form, concentration and route of administration of a
reference biological product and has proven through a comparability program that its quality, safety
and efficacy is equivalent to a reference product when prescribed in a claimed indication.
Generic: Copies of chemical, small molecule medicinal products that are structurally and
therapeutically equivalent to an originator pharmaceutical product.
Reference Biological product: Product developed and registered on basis of full qualtity,
preclinical and clinical dossier and used by the manufacturer of the biosimilar product.
Comparability exercise: Head-to-head comparison of a biological product with a licensed
reference biological product with the goal to establish similarity in quality, safety, and efficacy.
Products should be compared in the same study using the same procedures.
Pilot batches: Batches of finished product manufactured by a procedure fully representative of and
simulating that to be applied to a full production scale batches.
Production scale batches: Batches of a finished product manufactured at production scale by
using production equipment in a production facility as specified in the dossier
Pharmacovigilance: The science and activities relating to the detection, assessment, understanding
and prevention of adverse effects or any other drug related problems.
Equivalence study: A trial with the primary objective of showing that the response to two or more
treatments differs by an amount which is clinically unimportant. This is usually demonstrated by
showing that the true treatment difference is likely to lie between a lower and an upper equivalence
margin of clinically acceptable differences.
IV. Registration of a biosimilar product
Two approaches are applied for registration of biosimilar products:
1- Final dossier approach (for imported products):
Development process has been already done under supervision of the NRA of manufacturer
country of origin and only evaluation of the final product is done.
Page 5 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
2- Step wise approach (for locally manufactured products):
Development and registration processes proceed side by side; the process will be evaluated as
phases as follows:
1- Submit the Active substance master file & SMF for evaluation (Evaluation in this stage
depends on achieving quality requirements regardless of demonstrating biosimilarity), if
approved complete the next steps.
2- Full CMC including stability studies should be performed on suitable number of batches
(at least 3 pilot batches and 3 production batches; none of them will be marketed) of the
biosimilar product in addition to head to head comparability quality exercise with suitable
number of batches of the reference product, if approved complete the next steps .
3- Submit the CMC with the comparability quality data, Preclinical data & clinical protocol
for evaluation, if approved complete the next steps.
4- Submit Clinical studies for evaluation.
Phase 1
Box Approval
Phase 2
Pricing Phase
Phase 3
Product evaluation phase
Phase 4
Reports collection & Tech. committee
submission
Issuing registration license phase
Phase 1
Box Approval
Phase 2
Pricing Phase
Phase 3
Drug substance evaluation phase
Phase 4
CMC, Preclinical & Clinical protocol
evaluation phase
Phase 5
Admin, Clinical studies & PV
system Evaluation phase
Phase 6
Reports collection & Tech.
committee submission
Issuing registration
license phase
Page 6 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
V. Principles for Development of Biosimilar products
Development of biosimilar product and the responsibility of proving biosimilarity relys on the
manufacturer of the drug product, whether the drug substance manufacturer is the same entity of
the drug product manufacturer or a contract manufacturer, If the manufacturer of the drug
substance differs from that of the drug product, it will be the applicant’s responsibility to submit
active substance master file to the authority.
1- Select a reference product:
- A single reference product must be used for all comparability exercises during the
development process (i.e. quality, safety and efficacy).
- The reference product should be justified by the manufacturer of the biosimilar product
according to the following criteria:
Should be authorized on basis of complete dossier (full Quality, Preclinical and Clinical
data), Therefore an approved biosimilar cannot be considered as a reference product.
Should be either Licensed in Egypt or licensed and widely marketed in a reference
country for at least 4 year.
Should have the same dosage form, strength, and route of administration of the
biosimilar product intended to be developed.
2- Manufacturing Process and Expression system:
- The manufacturing process of the biosimilar product should employ state-of-the-art science
and technology to achieve a high quality biosimilar product that is as similar as possible to
the reference product.
- In case of recombinant products, Expression of the biosimilar product in the same host cell
type of the reference product is expected to produce a product that will encode the same
primary amino acid sequence.
- Changing the host cell type for development of a biosimilar product could be possible only if
the manufacturer can provide a convincing data proving that the structure of the molecule is
not affected and that the clinical profile of the product will not change. For example,
somatropin produced in yeast cells appears to have similar characteristics to somatropin
expressed in E. coli.
- However, the use of a different host cell type will not be feasible for glycoproteins because
glycosylation patterns vary significantly between different host cell types. For example, the
expression system can have a significant effect on the types and extent of translational and
post-translational modifications that are imparted to the proposed protein product.
Page 7 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
- The following guidelines for should be considered in the development process:
a. ICH Q5D Derivation and characterisation of cell substrates used for production biotechnological /biological
products.
b. ICH Q5B Quality of biotechnological products: analysis of the expression construct in cells used for production of r-
dna derived protein products.
c. ICH Q5A (R1) Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin
shall be followed for cell line qualification .
d. ICH Q11: Development and manufacture of drug substances–chemical and biotechnological/ biological entities.
VI. Comparability Key elements
- Complete CMC data should be submitted in CTD format according to ICH guidelines in addition
to quality comparability exercise with the reference product
- Head to head preclinical and clinical comparative studies with the same reference product used in
the Quality comparability exercise should be submitted. The quantity of the studies required
depends mainly on the outcomes of the quality data (for ex. differences in impurities or excipients may
have a potential impact on clinical safety and efficacy of the biosimilar product and a justification for allowing such
differences should be provided).
- Differences in quality pattern between the biosimilar and the reference product of unknown
clinical relevance, particularly regarding safety should be addressed in additional studies pre-
marketing.
- Differences in quality pattern between the biosimilar and the reference product that is known to
have potential impact on clinical activity will influence the judgment whether to consider the
product as a biosimilar or not. For example, if differences are found in glycosylation patterns that alter the bio
distribution of the product and thereby change the dosing scheme, then this product cannot be considered a
biosimilar product.
1- Quality Aspects:
Level of comparability studies (drug substance and drug product level):
- Comparability exercise has to be performed on both active substance and drug product
level.
- Product characterization studies should be performed using state of the art of the analytical
methods on the most intermediate best suited for the analytical procedures used.
- If the finished drug product is best suited for a particular analysis, the characterization
should compare the proposed finished biosimilar product and the finished reference product.
- If the finished product is not suitable for characterization methods; comparability exercise
may have to be performed on the active substance, the manufacturer may have to extract the
drug substance from the reference finished product.
Page 8 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
- Comparative deformulation could be applied for extraction taking into consideration that
the applicant should describe the extraction procedure of the drug substance from the
reference product and provide support that the extraction procedure itself does not alter
product quality. This would include consideration for alteration or loss of the desired
products and impurities and relevant product-related substances, and it should include
appropriate controls that ensure the relevant product characteristics of the reference product
are not significantly altered by the extraction procedure.
Analytical studies carried out to support the approval of a proposed biosimilar product should
be part of a broad comparison that includes, but is not limited to, the proposed biosimilar
product, the reference product, applicable reference standards, and consideration of relevant
publicly available information.
A. Structural characterization and conformation
- A comprehensive set and combination of analytical methods are used
- Generally characterization tests include but not limited to:
Primary structures, such as amino acid sequence, N and C-terminal sequence Higher
order structures, including secondary, tertiary, and quaternary structure (including
aggregation) .
Enzymatic post-translational modifications, such as glycosylation and
phosphorylation.
Other potential variants, such as protein deamidation and oxidation.
Intentional chemical modifications, such as PEGylation sites and characteristics.
B. Specifications: Release of DS / DP
- Appropriate analytical test methods should be selected based on the nature of the protein
being characterized and knowledge regarding the structure and heterogeneity of the
reference and the proposed biosimilar product following the ICH guidelines: Q6B
Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological
Products
- Extensive analytical characterization for different batches of the reference product
should be perform, this would enable the applicant to:
Detect batch to batch variation within batches of the same reference product.
Specify the acceptance criteria for biosimilarity with justification
Page 9 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
- Specifications for the biosimilar product should be set based on the obtained data for the
biosimilar and the applicant’s own experimental results obtained by testing the reference
product
- Specifications should not be wider than the range of variability of the reference product
- Each acceptance criterion should be established and justified based on data obtained
from lots used in nonclinical and/or clinical studies, and by data from lots used for
the demonstration of manufacturing consistency, data from stability studies, relevant
development data and data obtained from the comparability exercise
- Methods used for setting specifications may or may not be same as analytical methods
used for product characterization and for establishing product comparability
This comparability testing regarding specifications includes:
Physicochemical properties
includes but not limited to (Molecular weight / size , Isoform pattern , Extinction
coefficient , Electrophoretic patterns , Liquid chromatographic patterns ,
Spectroscopic profiles).
Biological activity (potency)
Appropriate biological assays are required to characterize the activity and establish
the product’s mechanism of action and clinical effects (in units of activity)
Assays should be calibrated against an international or national reference standard,
where available and appropriate. If no such standards are available, an internal
reference standard must be established as per the ICH guidelines.
These assays should comply with appropriate European Pharmacopoeia requirements
for biological assays, if applicable.
It includes but not limited to (Animal-based biological assays, Cell culture-based
bioassays, Biochemical and biophysical assays).
Immunochemical properties
includes but not limited to (Binding assays of the antibody to antigen, Affinity,
avidity and immune-reactivity (including cross-reactivity)
Purity and impurities
Information based on the analysis of samples stored under stress conditions,
inducing selective degradation (e.g., oxidation, dimerization) should be used for
identification. Comparison of product related substances, and of product-related
impurities should be based on specific degradation pathways and potential post-
translational modifications of the individual proteins. Accelerated stability studies
Page 10 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
of the reference and of the biosimilar product can be used to further define and
compare stability profiles
Impurities is either Process-related or Product-related (process-related impurities do
not form part of the comparability exercise; however they must be controlled for as
part of biosimilar manufacture) it includes but not limited to Aggregation,
Deamidation, Oxidation, Truncation, Charge variants, Visible, sub-visible and sub-
sub visible particles
C. Final formulation
- The acceptability of the type, nature, and extent of any differences between the proposed
finished biosimilar product and the finished reference product should be evaluated
- Different excipients in the proposed product should be supported by existing toxicology
data for the excipient or by additional toxicity studies with the formulation of the
proposed biosimilar product
- Differences in formulation between the proposed biosimilar product and the reference
product are among the factors that may affect whether subsequent clinical studies may
take a selective and targeted approach
“Release tests should be validated according to the ICH guideline: Q2 (R1) Validation of
analytical procedures: text and methodology. If available, standards and reference
materials (e.g., from Ph. Eur., WHO, etc.) should be used for method qualification and
validation”
D. Stability
- Complete stability studies for drug substance and drug product following “ICH guideline
Quality of biotechnology products: stability testing of biotechnological/biological
products QC5” should be conducted.
- Side-by-side accelerated and stressed studies comparing the biosimilar product to the
reference product will be of value in determining the similarity of the products by
showing comparable degradation profiles.
- Any claims with regard to stability and compatibility cannot be extrapolated from the
reference product and must be supported by data.
Page 11 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
2- Preclinical Aspects
The design of an appropriate pre-clinical study program requires a clear understanding
of the product characteristics outcomes from the quality comparability data and depends on
the product class. Generally the spectrum of studies required to establish safety & efficacy of
the biosimilar product may vary considerably & should be defined case-by-case basis
A. Factors affecting design of the preclinical comparability program include but not
limited to:
Quality-related factors:
Significant differences in the cell expression system compared with the reference
product
Significant differences in purification methods used
The presence of a complex mixture of less well characterized product- and/or process
related impurities
Factors related to pharmaco-toxicological properties of the drug substance:
- Mechanism(s) of drug action are unknown or poorly understood
- The drug substance is associated with significant toxicity and/or has a narrow
therapeutic index
- Limited clinical experience with the reference product
B. General considerations:
- Pre- clinical studies should be head to head comparative studies between the biosimilar
and reference product
- More than one aspect of comparability can be addressed in one study depending on the
study design (which considers the objective(s), Evaluation criteria, system used...)
- Performing preclinical studies should take into consediration “ICH guideline: Note for
preclinical safety evaluation of biotechnology-derived pharmaceuticals` (ICH S6)”
C. The minimum pre-clinical studies required for evaluating a biosimilar product are:
a) In Vitro studies: (Pharmacodynamic Studies):
Assays like receptor-binding studies or cell-based assays, Such data may already be
available from quality-related bioassays.
Page 12 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
b) In Vivo studies: (Pharmacodynamic/ Toxicologic/ Immunogenicity Studies):
As a basis to decide to what extent non-clinical in vivo pharmacodynamic and/or
toxicological studies should be part of the comparability exercise, the applicant should
consider a risk-based approach which takes into account:
- Specific pharmaco-toxicological properties of the active substance.
- The feasibility and relevance of comparative/non-comparative in vivo testing in a
relevant species.
In vivo studies are performed to address:
Non clinical toxicity
- At least one repeat dose toxicity study in relevant species is required to be conducted.
- Selection of species should follow ICH guideline preclinical safety evaluation of Biotechnology –
derived pharmaceuticals S6(R1) section 3.3
- The duration of the study should be based on the intended duration of clinical exposure
and disease indication.
1-3 months for most products.
Two weeks for products intended for short-term use ( e.g., < to 7 days) and for
acute life-threatening diseases
Pharmacodynamic effect
Activity relevant to clinical indication (can be waived if the available in vitro assays have
been validated to reliably reflect the clinically relevant pharmacodynamic activity of the
reference product)
Local tolerance
Evaluated depending on the route of administration, could be part of the repeat dose
toxisity study.
Immunogenicity Generally animal immunogenicity assessments do not predict potential immunogenic
responses to protein products in humans. While antibody measurements, if applicable,
should be included in the repeat dose toxicity study to aid in the interpretation of the
toxico-kinetic data.
Generally other routine toxicological studies such as safety pharmacology, reproductive
toxicology, genotoxicity and carcinogenicity studies are not required, unless triggered by results
Page 13 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
of the repeat dose toxicity study or the local tolerance study and/or by other known toxicological
properties of the reference product (e.g. known adverse effects of the reference product on
reproductive function)
D. Batches:
- Preclinical studies should be conducted with the final formulation
- Types of batches required to conduct preclinical studies are the production batches used
in the quality comparability.
3- Clinical Aspects:
The scope and extent of clinical studies will depend on the outcomes of the comparability
quality and preclinical data.
A. General Considerations:
- Clinical studies should be head to head comparative studies between the biosimilar and
reference product
- The clinical comparability exercise is a stepwise procedure that should begin with
pharmacokinetic (PK) and pharmacodynamics (PD) studies followed by clinical efficacy
and safety trial(s) or, in certain cases, pharmacokinetic/pharmacodynamics (PK/PD)
studies for demonstrating clinical comparability.
- More than one aspect of comparability can be addressed in one study depending on the
study design (which considers the objective(s), Evaluation criteria, Type of population...)
- Performing clinical studies should follow ICH guidelines taking into consideration the
following:
a) It must be reasonably assured that if a difference between the reference product and
biosimilar product exists, then the study is capable of showing that difference.
b) Route of administration selected (should be the most sensitive route; justification
should be submitted)
c) Dose determination: using dose/doses within the steep part of the dose-response curve
in order to best detect potential differences between the biosimilar and the reference
product).
d) Type of population included in the study could be healthy or patients but it should be
taken into consideration the choice of sensitive population that is able to detect
potential differences between the biosimilar and the reference product. (for ex. In case of
Page 14 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
insulin, the study population should consist of non-obese healthy volunteers or patients with type
1diabetes rather than insulin-resistant obese patients with type 2 diabetes)
B. Clinical study should address the following aspects:
a) PK parameters:
- All (ADME) parameters should be investigated. (other PK studies such as interaction
studies or studies in special population are generally not required)
- Acceptance criteria for the demonstration of similar PK between the Biosimilar
product and the Reference product should be pre-defined, justified and and clearly
documented in the study protocol. (It is noted that the criteria used bioequivalence studies
were developed for chemically-derived, orally administered products and may not necessarily be
applicable for biological medicinal products. Meanwhile, due to the lack of established acceptance
criteria designed for biologicals, the traditional 80- 125 % equivalence range is often used. However,
if the 90% confidence intervals of the ratio of the population geometric means (test/ reference) for the
main parameters under consideration (usually rate and extent of absorption) fall outside this
traditional range, the biosimilar may still be considered similar to the reference product provided
there is sufficient evidence for similarity from the quality, non-clinical, PD, efficacy and safety
comparisons).
- PK studies should generally be performed for the routes of administration applied
for.
- PK studies should generally be performed using doses within the therapeutic dose
range recommended for the reference product.
- The choice of single-dose studies, steady-state studies, or repeated determination of
PK parameters and the study population should be justified by the manufacturer. (It
should be noted that single dose study is not suitable for measuring immunogenicity)
- The ordinary cross-over design may not be appropriate for biological medicinal
products with a long half-life or for proteins for which formation of anti-product
antibodies is likely.
b) PD markers:
- The pharmacodynamics (PD) markers should be selected on the basis of their
relevance to demonstrate therapeutic efficacy of the product. For ex. absolute neutrophil
count and CD34+ cell count are the relevant PD markers for the activity of granulocyte colony
stimulating factor (G-CSF) and could be used in PK/PD studies in healthy volunteers to demonstrate
similar efficacy of two G-CSF-containing medicinal products
- In many cases, PD parameters are investigated in the context of combined PK/PD
studies. Such studies may provide useful information on the relationship between
dose/exposure and effect, particularly if performed at different dose levels.
Page 15 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
c) Efficacy:
- Clinical efficacy studies should be adequately powered, randomized, and controlled
trial(s).
- Studies should preferably be double-blind or at a minimum observer-blind. (In the
absence of any blinding, careful justification will be required to prove that the trial results are free
from significant bias)
- Equivalence designs are preferred for the comparison of efficacy & safety of
biosimilar & reference product, In case of using non-inferiority designs justification should be
submitted
- Equivalence/ non-inferiority margins have to be pre-specified & justified. i.e. The
selected margin should represent the largest difference in efficacy that would not matter in clinical
practice.
d) Safety:
- Pre-licensing safety data should be obtained in a sufficient number of patients to
characterize the safety profile of the biosimilar product. Depending on their size and
duration, efficacy trials may be sufficient or may need to be extended to provide an
adequate safety database.
- Comparison with the reference product should include type, frequency and severity
of adverse events/reactions.
- Further close monitoring of clinical safety of the biosimilar is usually necessary in
the post-marketing phase.
e) Immunogenicity:
(Two studies should be conducted one preauthorization and one post authorization;
the preauthorization study should be comparative the post authorization study could
be stand-alone)
- The consequences of unwanted immunogenicity may vary considerably, ranging
from clinically irreverent to serious & life threatening diseases.
- Generally, the amount of immunogenicity data obtained from comparative efficacy
trial(s) will allow detection of a marked increase in immunogenicity of biosimilar
compared to reference product & will be sufficient pre-licensing.
- In case similar efficacy is demonstrated in confirmatory PK/PD study(ies),
immunogenicity data in the target population are still needed.
Page 16 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
- The required observation period for immunogenicity testing will depend on:
a. The intended duration of therapy (In case of chronic administration, one-year data will
usually be appropriate pre-licensing to assess antibody incidence & possible clinical
implications)
b. The expected time of antibody development ( should be justified by the
manufacturer)
A confirmatory clinical study is required to demonstrate biosimilarity, this study can
be waived if all the following conditions are met:
- PK of reference product are well characterized and the relationship between
dose/response and response/efficacy of the reference product “concentration – response”
curve is known, e.g. from literature
- Structural and functional comparability of biosimilar and reference product can be
characterized to a high degree of confidence by physicochemical and in vitro techniques
- The biosimilar product is comparable to the reference product in all preclinical
evaluations conducted
- PK / PD study has demonstrated comparability and has preferentially been done in an
inpatient setting with safety measurement (including immunogenicity) for adequate
period justified by the applicant and efficacy measurements
- A comprehensive post marketing risk management plan has been presented that will
gather additional safety data with a specific emphasis on gathering immunogenicity data
- At least one PD marker is accepted as a surrogate marker for efficacy, and the
relationship between dose/exposure to the product and this surrogate marker is
well known.
If at any step relevant differences between the biosimilar product and the reference product
are detected, the reasons need to be explored and justified. If this is not possible, the new
product may not qualify as a biosimilar product and a stand-alone application should be
considered.
C. Batches:
- Clinical studies should be conducted with the final formulation
- Types of batches required to conduct clinical studies are production scale batches used
in the quality and pre-clinical comparability exercise.
Page 17 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
D. Extrapolation of indication could be possible if all the following conditions are met:
a) A sensitive population criterion that is able to detect potential differences between the
biosimilar and reference product is used. e.g. In case of Growth hormone, treatment-naïve
children with GH deficiency usually represent the most appropriate study population as opposed to
children with non GH-deficient short stature that are usually less sensitive to the effects of GH. Although
adult patients with GH deficiency could also be considered a “sensitive” population, the endpoint used
to measure effects of GH treatment (i.e. body composition) is less sensitive than the one used in children
(i.e. longitudinal growth) making an equivalence margin more difficult to define.
b) The clinically relevant mechanism of action and/or involved receptor(s) are the same
which addresses but not limited to the following:
- target/receptor(s) for each relevant activity/function of the product
- the binding, dose/concentration response and pattern of molecular signaling upon
engagement of target/receptors
- the relationships between product structure and target/receptor interactions
- the location and expression of the target/receptor(s);
c) Safety and immunogenicity of the biosimilar product have been investigated in the
patient population that carries the highest risk of an immune response and immune-
related adverse events, thus sufficiently characterized and there are no
unique/additional safety issues expected for the extrapolated indication(s).
d) The efficacy trial used a non-inferiority study design and demonstrated acceptable
safety and efficacy of the biosimilar compared to the reference product, the applicant
should provide convincing arguments that this finding can be applied to the
extrapolated indications.
If the above mentioned conditions for extrapolation of efficacy and safety data of the
biosimilar to other indication(s) of the reference are not fulfilled, the applicant will
need to submit own clinical data to support the desired indication(s).
VII. Pharmacovigilance
Product pharmacovigilance plan according to the EPVC guidelines should be submitted;
this plan should include protocol for post marketing immunogenicity study at the time of
submission of the marketing authorization application.
Page 18 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
VIII. Glossary
ICH: International Conference on Harmonisation
CAPA: Central Administration for Pharmaceutical Affairs
NORCB: National Organization for Research and Control of Biologics
ASMF: Active substance master file
SMF: Site Master File
CMC: Chemistry, Manufacturing and Control
NRA: National Regulatory authority
EPVC: Egyptian Pharmacovigilance Center
RMP: Risk management plan
PSUR: Periodic Safety Update Report
PK: Pharmacokinetic
ADME: Absorbtion, Distribution, Metabolism, Elimination
PD: Pharmacodynamic
NRA: National Regulatory Authority
Page 19 of 19
وزارة الصحة
اإلدارة المركسية للشئون الصيدلية
للتسجيل العبمة اإلدارة
تسجيل المستحضرات الحيوية إدارة
Ministry of Health
Central Administration for
Pharmaceutical Affairs
General Registration Department
Department of Biological
Products Registration
Tel.: +202 – 23684288 +202 – 23648769 +202 – 23640368 Ext.:1330 Fax: +202 - 23684194
Website: www.eda.mohp.gov.eg Version: 0.1 Email: [email protected]
Reference guidelines
WHO- GUIDELINES ON EVALUATION OF SIMILAR BIOTHERAPEUTIC PRODUCTS
ICH guidelines
- ICH S6- Pre-clinical safety Evaluation of Biotechnology-derived pharmaceuticals
- ICH E8- General consideration for clinical trials
- ICH E9- Statistical principles for clinical trials
- ICH Q5C - Quality of Biotechnological products: Stability testing of
Biotechnological/Biological products
- ICH Q5D - Derivation and characterization of cell substrates used for production of
Biotechnological/Biological products
- ICH Q5A - Viral safety evaluation of Biotechnology products derived from cell lines of
human and Animal origin
- ICH Q5B Quality of biotechnological products: analysis of the expression construct in cells
used for production of r-dna derived protein products
- ICH Q11- Development and manufacture of drug substances (chemical entities and
biotechnological/biological entities
EMA-Overarching biosimilar guidelines
EMA- Product-specific biosimilar guidelines
EMA- Other guidelines relevant for biosimilars
EMA- Scientific Guidelines on Biological Drug substances
EMA- Scientific Guidelines on Biological Dug Products
FDA- Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product
FDA- Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
CDSCO- Indian Biosimilars Guidelines
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